A. Sadegphour (Author), Michael Rappolt (Author), Dimitrios Ntountaniotis (Author), Petros Chatzigeorgioug (Author), Kyriakos Viras (Author), Grigorios Megariotis (Author), M. Papadopoulos (Author), Eleni Siapi (Author), Gregor Mali (Author), Thomas Mavromoustakos (Author)

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin is the rate limiting enzyme of the RAAS and aliskiren is a highly potent and selective inhibitor of the human renin. Renin is known to be active both in the circulating blood stream as well as locally, when bound to the (pro)-renin receptor ((P)RR). In this study we have investigated a possible mechanism of action of aliskiren, in which its accumulation in the plasma membrane is considered as an essential step for effective inhibition. Aliskiren's interactions with model membranes (cholesterol rich and poor) have been investigated by applying different complementary techniques: differential scanning calorimetry (DSC), Raman spectroscopy, magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy and small- and wide-angle X-ray scattering (SAXS and WAXS). In addition, in silico molecular dynamics (MD) calculations were applied for further confirmation of the experimental data. Aliskiren's thermal effects on the pre- and main transition of dipalmitoyl-phosphatidylcholine (DPPC) membranes as well as its topographical position in the bilayer show striking similarities to those of angiotens.in II type 1 receptor (AT1R) antagonists. Moreover, at higher cholesterol concentrations aliskiren gets expelled from the membrane just as it has been recently demonstrated for the angiotensin receptor blocker (ARB) losartan. Thus, we propose that both the AT1R and the (P)RR-bound renin active sites can be efficiently blocked by membrane-bound ARBs and aliskiren when cholesterol rich membrane rafts/caveolae are formed in the vicinity of the receptors.

Keywords

aliskiren;renin;PRR;DPPC bilayers;raman spectroscopy;solid state NMR spectroscopy;SAXS and WAXS;MD simulations;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: KI - National Institute of Chemistry
UDC: 577.2
COBISS: 5618202 Link will open in a new window
ISSN: 0005-2736
Views: 3808
Downloads: 184
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Other data

Secondary keywords: zgradba molekule;receptorji;lipidi;
Type (COBISS): Article
Source comment: Sodelavci: M. Rappolt, D. Ntountaniotis, P. Chatzigeorgiou, K. Viras, G. Megariotis, M. G. Papadopoulos, E. Siapi, G. Mali, and T. Mavromoustakos;
Pages: str. 984-994
Volume: ǂVol. ǂ1848
Issue: ǂiss. ǂ4
Chronology: Apr. 2015
DOI: 10.1016/j.bbamem.2014.12.004
ID: 9145164